Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease

Abstract

Cowden disease, also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome with a high risk of breast and thyroid cancer. The gene involved has been localized to chromosome 10q22-23. Recently, the tumour suppressor gene PTEN/MMAC1, encoding a putative protein tyrosine or dual-specificity phosphatase, was cloned from that region and three mutations were detected in patients with Cowden disease. We confirmed that the PTEN/MMAC1 gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN/MMAC1 gene and, by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various regions of the PTEN/MMAC1 gene. One mutation was detected twice. All detected changes in the gene can be predicted to have a very deleterious effect on the putative protein. Five of the nine patients have a mutation in exon 5 coding for the putative active site and flanking amino acids. Evaluation of the clinical data of the patients in which a mutation could be detected gives no clear indications for a correlation between the genotype and phenotype. In 10 patients no mutation could be detected so far. In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogeneity.

Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

“…Furthermore, previous studies have reported frequent loss of heterozygosity at chromosome 10q23 in endometrial and thyroid cancers (Simpkins et al, 1998). This gene is considered to act as a tumour suppressor gene in the pathogenesis of multiple cancers for several reasons: (i) This gene is frequently mutated in tumours arising in patients with Cowden disease and the Bannayan-Zonana syndrome, which are both characterized as hereditary syndromes leading to multiple hamartomas in the case of Cowden disease and both exhibit an increased risk of developing breast, thyroid and skin cancer Lynch et al, 1997;Marsh et al, 1997;Nelen et al, 1997). (ii) PTEN has been shown to act against phosphatidylinositol phosphates, pointing to a role of PTEN as a mediator of the phosphatidylinositol kinase pathway (Myers et al, 1997;Maehama and Dixon, 1998).…”

“…Thus, the reduced expression of PTEN may result from hypermethylation of the PTEN promotor, the enhanced degradation of the transcript or the transcriptional inactivation of the gene (Lynch et al, 1997;Whang et al, 1998). For instance, in Cowden disease, nonsense-mediated degradation of the gene was reported Lynch et al, 1997;Nelen et al, 1997). In addition, in a study using prostate cancer tissues and cell lines, the treatment of the cells with the demethylating agent 5-azadeoxycytidine led to the restoration of PTEN mRNA levels, which reflects a possible role of hypermethylation of the promotor in the regulation of PTEN transcription (Whang et al, 1998).…”

“…In addition, recent studies indicate that PTEN may function as a mediator of the phosphatidylinositol (PI3') kinase pathway (Maehama and Dixon, 1998). These findings, along with the description of germline mutations and deletions of PTEN in two hereditary cancer predisposition diseases Marsh et al, 1997;Nelen et al, 1997), i.e. Cowden Disease and the Bannayan-Zonana-syndrome, point to a role of PTEN as a tumour suppressor gene in the pathogenesis of malignant tumours.…”

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

“…Germ-line mutations of PTEN cause three autosomal dominant disorders, Cowden disease, Lhermitte-Duclos disease and Bannayan-Zonana syndrome, all of which form benign tumors in a variety of tissues with increased risk for cancer development Nelen et al, 1997;Marsh et al, 1998). PTEN is also essential for embryonic development: Its inactivation by gene targeted disruption in mouse resulted in early embryonic lethality, and Pten þ /À mice showed hyperplastic-dysplastic changes in many tissues (Di Cristofano et al, 1998).…”

A novel germline mutation of PTEN associated with brain tumours of multiple lineages

“…Mutation of PTEN appears to occur early in tumour development in endometrial cancer but late in the development of gliomas. Germline mutations in PTEN have also been found in the dominantly inherited Cowden, LhermitteDuclos, and Bannayan-Zonana syndromes, which are characterised by the formation of multiple benign tumours (Nelen et al, 1997).…”